Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

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This clinical trial studies nivolumab and ipilimumab in treating patients with rare tumors. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.

II. To describe the mutational load and targeted sequencing of well-known oncogenes and changes in these markers of patients at up to three time points (baseline, cycle 2, and progression), and across strata to describe associations with survival outcomes.

III. To describe the presence of germline mutations, and across strata to evaluate association with outcome.

IV. Within strata, to describe patient risk category as defined by the biodesix protein signature and change over time at up to three time points (baseline, cycle 2, progression), and across strata to evaluate associations with outcomes.

V. Within strata, to evaluate the association of PD-L1 expression (positive versus negative) with response and survival outcomes, and within strata, to characterize baseline PD-L1 prevalence.

VI. To collect specimens for banking for use in future correlative biomarker research studies.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 10 years from registration.

Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).

Overall survival (OS), estimated using both RECIST and irRC [ Time Frame: From date of registration to date of death due to any cause, assessed up to 10 years ]

Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).

Progression free survival (PFS), estimated using both RECIST and irRC [ Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration or death, assessed up to 10 years ]

Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients are eligible under ONE of the following criteria:

Patients must have histologically confirmed rare cancer and must be able to submit specimens; NOTE: Subsequent to site's Institutional Review Board (IRB) approval of revision 3, patients are NOT required to participate in EAY131 "National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (MATCH)" to register to this study

FOR PATIENTS ENROLLED IN EAY131 "NCI-MATCH" PRIOR TO EAY131 ADDENDUM 10 ONLY: Patients must have histologically confirmed rare cancer that did not have a match to a molecularly-guided therapy on EAY131 "NCI-MATCH" protocol or who are off protocol treatment on EAY131, "NCI-MATCH" and have no further molecularly-matched treatment recommendations per EAY131, "NCI-MATCH" or who are otherwise unable to receive EAY131, "NCI-MATCH" therapy

Patients that do not qualify for one of the histologic cohorts may be considered for registration in the "Not Otherwise Categorized" Rare Tumors cohort with confirmation of at least one of the study chairs via email

Patients that are determined to have a rare cancer with unknown primary site are eligible under cohort #32 (tumor of unknown primary [cancer of unknown primary; CuP]), provided that there is histologic documentation of metastatic malignancy with no discernible primary site identified from histopathologic review, physical exam and associated cross-sectional imaging of the chest, abdomen, and pelvis

Patients must have progressed following at least one line of standard systemic therapy and there must not be other approved/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolonged survival due to medical issues will be eligible, if other eligibility criteria are met; OR

Patients for whose disease no standard treatment exists that has been shown to prolong overall survival

Patients must have a diagnostic quality computed tomography (CT) scan or magnetic resonance imaging (MRI), performed within 28 days prior to registration, which demonstrates measurable disease, as defined in RECIST v. 1.1; all disease must be assessed and documented on the S1609 Baseline Tumor Assessment Form

No other prior malignancy is allowed except for the following:

Adequately managed stage I or II cancer from which the patient is currently in complete remission

Any other cancer from which the patient has been disease free for one year

Adequately managed stage I or II follicular thyroid or prostate cancer is also eligible, wherein patient is not required to be in complete remission

Patients may have received prior anti-CTLA4 or other anti-PD-1/anti-PD-L1 therapy, not both, provided that it is completed >= 4 weeks prior to registration

Patients are not eligible if they have had or are planned for solid organ transplant; patients who have received allogeneic hematopoietic stem cell transplant are eligible if:

The transplant occurred at least 90 days prior to registration,

Patient has no prior acute graft versus host disease (GVHD), and

Within 48 hours of registration, patient demonstrates at least 90% engraftment, defined as: absolute neutrophil count (ANC) >= 500 mcl, measured over 3 consecutive days or 1 day with an ANC >= 1,000 mcl, or platelets >= 50,000 mcl measured, wherein the patient did not receive any platelet transfusions within 7 days prior to laboratory assessment

Patients with autoimmune disease who are otherwise eligible must not have received steroid and immunosuppressive therapy within 28 days prior to registration

Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 28 days prior to registration and have stable disease at time of registration; metastatic brain parenchymal disease must have been treated and patient must be off steroids for 7 days prior to registration; patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration

Patients must not currently be receiving any other investigational agents or any other systemic anti-cancer therapy (including radiation, excluding RANKL inhibitors and bisphosphonates); in event patient recently received any other systemic anti-cancer therapy, patient must be off therapy at least 7 days prior to registration and any therapy-induced toxicity must have recovered to =< grade 1, except alopecia and =< grade 2 neuropathy which are allowed; any planned radiation therapy must be completed before enrollment onto S1609

Patients must not have prior history of allergy or known hypersensitivity to nivolumab or ipilimumab

Within 28 days prior to registration: Creatinine clearance (CrCl) >= 50 mL/min., as estimated by the Cockcroft and Gault formula; estimated creatinine clearance is based on actual body weight

Patients must have adequate thyroid function, as evidenced by either thyroid-stimulating hormone (TSH) or, free thyroxine (T4) serum tests demonstrating values within the normal range, within 28 days prior to registration; Note: TSH, with reflex T4 is allowable if per institutional standard; otherwise, both TSH and free-T4 must be obtained

Females of childbearing potential must have negative serum or urine pregnancy test 7 days prior to registration and agree to use birth control throughout study and for 23 weeks after completion of protocol therapy; patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

Men of reproductive potential must have agreed to use birth control throughout the study and for 31 weeks after completion of protocol therapy; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (vasectomy); however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he is responsible for beginning contraceptive measures

Patients must not have known active hepatitis B virus (HBV) or hepatitis virus (HCV) infection at time of registration; patients with HBV or HCV that have an undetectable viral load, or in the opinion of the treating investigator is well-controlled, are eligible

Patients who are known to be human immunodeficiency virus (HIV)-positive at registration are eligible at the time of registration:

If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; once daily combinations that use pharmacologic boosters may not be used

No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts

Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10mg or equivalent); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory bowel disease (including ulcerative colitis and Chron's disease), as well as symptomatic disease (e.g. rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis or glomerulonephritis); vitiligo, alopecia, hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not requiring systemic therapy within the past 2 years is permitted; short-term steroid premedication for contrast allergy is permitted

Note: Patients with history of CHF or patients who are deemed at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs should have an electrocardiogram (EKG) and echocardiogram (ECHO), as clinically indicated, at baseline and at the start of each cycle; patients who have evidence at baseline (or subsequently) of CHF, myocardial infarction (MI), cardiomyopathy, or myositis cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist, including review of EKG, creatine phosphokinase (CPK), troponin, echocardiogram, as clinically indicated

Patients must have amylase or lipase within =< 1.5 x IULN without symptoms of pancreatitis at registration, within 28 days prior to registration

Patients must not have symptomatic interstitial lung disease or pneumonitis

Patients must have fully recovered from any adverse effects of major surgery (to =< grade 1) at least 14 days prior to registration